CN108276405A - A kind of synthesis technology of medicine intermediate imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester - Google Patents
A kind of synthesis technology of medicine intermediate imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester Download PDFInfo
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- CN108276405A CN108276405A CN201810201551.2A CN201810201551A CN108276405A CN 108276405 A CN108276405 A CN 108276405A CN 201810201551 A CN201810201551 A CN 201810201551A CN 108276405 A CN108276405 A CN 108276405A
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- pyridine
- added
- ethyl ester
- carboxylic acids
- imidazo
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- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 10
- 239000003814 drug Substances 0.000 title claims abstract description 10
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 10
- 238000005516 engineering process Methods 0.000 title claims abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 45
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims abstract description 10
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 9
- 235000019441 ethanol Nutrition 0.000 claims abstract description 8
- -1 (2H)-pyridyl Chemical group 0.000 claims description 14
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 239000012153 distilled water Substances 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000376 reactant Substances 0.000 abstract description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract 1
- 125000004494 ethyl ester group Chemical group 0.000 abstract 1
- 238000000034 method Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- VMMKGHQPQIEGSQ-UHFFFAOYSA-N minodronic acid Chemical compound C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 VMMKGHQPQIEGSQ-UHFFFAOYSA-N 0.000 description 2
- 229950011129 minodronic acid Drugs 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- JYEYKSKYVBLJQX-BENRWUELSA-N CCC(C=CC=C1)N1/C(/CC(C)(P(O)(O)=O)[P](C)(O)(O)=O)=C\N Chemical compound CCC(C=CC=C1)N1/C(/CC(C)(P(O)(O)=O)[P](C)(O)(O)=O)=C\N JYEYKSKYVBLJQX-BENRWUELSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- DCSBSVSZJRSITC-UHFFFAOYSA-M alendronate sodium trihydrate Chemical compound O.O.O.[Na+].NCCCC(O)(P(O)(O)=O)P(O)([O-])=O DCSBSVSZJRSITC-UHFFFAOYSA-M 0.000 description 1
- 150000004663 bisphosphonates Chemical class 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 229960003978 pamidronic acid Drugs 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical class O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention belongs to medicine intermediate fields, and in particular to a kind of synthesis technology of 2 carboxylic acid, ethyl ester of medicine intermediate imidazo [1,2 A] pyridine.The present invention can react after first mixing (2 oxo 1 (2H) pyridyl group) acetonitrile and Ethyl formate at low temperature, it is added in ethyl alcohol after reacting the reactants separate generated, and potassium carbonate is added, carry out back flow reaction, target product is obtained after reaction, easy to operate, mild condition of the invention, high income, purifying is convenient, product quality is excellent, and safety is good, reduces pollution.
Description
Technical field
The invention belongs to medicine intermediate fields, and in particular to a kind of medicine intermediate imidazo [1,2-A] pyridine -2- carboxylics
The synthesis technology of acetoacetic ester.
Background technology
Minodronic acid 2 (1- hydroxyls -2- (imidazo [1,2-a] pyridin-3-yl) ethane -1,1- two banks) is a kind for the treatment of
The hypercalcinemia caused by osteoporosis and malignant tumour belongs to third generation bisphosphonates.It is by Japanese Yamanouchi public affairs
The new type heterocycle double phosphinic acid compounds of exploitation are taken charge of, which is incadonate sodium, sodium alendronate respectively
With 2 times, 10 times and 100 times of Pamidronate Disodium.Due to the excellent curative effect of the product and smaller stomach side effect, make it have
Extensive potential applicability in clinical practice.
Imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester is the key intermediate for preparing minodronic acid, and therefore, exploitation is a kind of
Raw material is cheap and easy to get, easy to operate, and reaction condition is mild, and production cost is low, and yield is high, is suitble to large-scale production, storage, production
The method of process safety is completely necessary.
Invention content
The technical problems to be solved by the invention：For imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester synthesis technology it is multiple
It is miscellaneous, it is cumbersome, the problem of low yield, provide a kind of conjunction of medicine intermediate imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester
At technique.
In order to solve the above technical problems, the technical solution adopted by the present invention is：
Synthetic route of the present invention is as follows：
Specific synthesis step is as follows：
(1) in molar ratio 1：5, (2- oxos -1 (2H)-pyridyl group) acetonitrile and Ethyl formate are weighed, three-necked flask is added
In, it is put into ice-water bath, controlled at 5~10 DEG C, and sodium ethoxide is added, be stirred to react 6~8h, to three-necked flask after reaction
Middle addition distilled water, stands overnight, and collects oil phase；
(2) in mass ratio 1:8, oil phase and ethyl alcohol mixing are weighed, potassium carbonate is added after mixing, is heated to flowing back, reflux is anti-
30~40min is answered, it is 4.5~5.0 that vinegar acid for adjusting pH value is used after reaction, and rotary evaporated to dryness after adjusting is collected solid, is washed with water
It is dry after washing, you can to obtain imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester.
The molar ratio of the sodium ethoxide and (2- oxos -1 (2H)-pyridyl group) acetonitrile is 5~7:1.
The potassium carbonate addition is the 10~20% of oil phase quality.
Compared with other methods, advantageous effects are the present invention：
(1) present invention can be into after first mixing (2- oxos -1 (2H)-pyridyl group) acetonitrile and Ethyl formate at low temperature
Row reaction, and synthetic method, without using catalyst, wherein Ethyl formate is liquid charging stock, be added before reacting it is excessive, then without
Other organic solvent need to be added, the processes such as separation, the recycling of organic solvent need not be carried out, simple for process, wherein sodium ethoxide can
Reaction response is promoted to carry out completely；
(2) reactant of (2- oxos -1 (2H)-pyridyl group) acetonitrile and Ethyl formate is added in ethyl alcohol, and carbonic acid is added
Potassium carries out back flow reaction, target product is obtained after reaction, easy to operate, mild condition of the invention, high income, purifying is convenient, production
Quality is excellent, and safety is good, reduces pollution.
Description of the drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester.
Fig. 2 is the carbon-13 nmr spectra figure of imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester.
Specific implementation mode
In molar ratio 1：5, (2- oxos -1 (2H)-pyridyl group) acetonitrile and Ethyl formate are weighed, is added in three-necked flask, puts
Enter in ice-water bath, controlled at 5~10 DEG C, and sodium ethoxide is added, sodium ethoxide and (2- oxos -1 (2H)-pyridyl group) acetonitrile
Molar ratio is 5~7:1, it is stirred to react 6~8h, distilled water is added after reaction into three-necked flask, is stood overnight, oil phase is collected；
In mass ratio 1:8, oil phase and ethyl alcohol mixing are weighed, 10~20% potassium carbonate of oil phase quality are added after mixing, are heated to flowing back,
30~40min of back flow reaction, it is 4.5~5.0 that vinegar acid for adjusting pH value is used after reaction, and rotary evaporated to dryness after adjusting collects solid,
It is dry after being washed with water, you can to obtain imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester.
Example 1
In molar ratio 1：5, (2- oxos -1 (2H)-pyridyl group) acetonitrile and Ethyl formate are weighed, is added in three-necked flask, puts
Enter in ice-water bath, controlled at 5 DEG C, and sodium ethoxide is added, mole of sodium ethoxide and (2- oxos -1 (2H)-pyridyl group) acetonitrile
Than being 5:1, it is stirred to react 6h, distilled water is added after reaction into three-necked flask, is stood overnight, oil phase is collected；In mass ratio 1:
8, oil phase and ethyl alcohol mixing are weighed, 10% potassium carbonate of oil phase quality is added after mixing, is heated to flowing back, back flow reaction 30min,
It is 4.5 that vinegar acid for adjusting pH value is used after reaction, and rotary evaporated to dryness after adjusting collects solid, dry after being washed with water, you can to obtain
Imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester, purity 99.3%, yield 87%.
Example 2
In molar ratio 1：5, (2- oxos -1 (2H)-pyridyl group) acetonitrile and Ethyl formate are weighed, is added in three-necked flask, puts
Enter in ice-water bath, controlled at 7 DEG C, and sodium ethoxide is added, mole of sodium ethoxide and (2- oxos -1 (2H)-pyridyl group) acetonitrile
Than being 6:1, it is stirred to react 7h, distilled water is added after reaction into three-necked flask, is stood overnight, oil phase is collected；In mass ratio 1:
8, oil phase and ethyl alcohol mixing are weighed, 15% potassium carbonate of oil phase quality is added after mixing, is heated to flowing back, back flow reaction 35min,
It is 4.7 that vinegar acid for adjusting pH value is used after reaction, and rotary evaporated to dryness after adjusting collects solid, dry after being washed with water, you can to obtain
Imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester, purity 99.5%, yield 89%.
Example 3
In molar ratio 1：5, (2- oxos -1 (2H)-pyridyl group) acetonitrile and Ethyl formate are weighed, is added in three-necked flask, puts
Enter in ice-water bath, controlled at 10 DEG C, and sodium ethoxide is added, sodium ethoxide rubs with (2- oxos -1 (2H)-pyridyl group) acetonitrile
You are than being 7:1, it is stirred to react 8h, distilled water is added after reaction into three-necked flask, is stood overnight, oil phase is collected；In mass ratio
1:8, oil phase and ethyl alcohol mixing are weighed, 20% potassium carbonate of oil phase quality is added after mixing, is heated to flowing back, back flow reaction
40min, it is 5.0 that vinegar acid for adjusting pH value is used after reaction, and rotary evaporated to dryness after adjusting collects solid, dry after being washed with water, i.e.,
Imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester, purity 99.6%, yield 89% can be obtained.
Claims (3)
1. a kind of synthesis technology of medicine intermediate imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester, it is characterised in that specific synthesis
Step is：
(1) in molar ratio 1：5, (2- oxos -1 (2H)-pyridyl group) acetonitrile and Ethyl formate are weighed, is added in three-necked flask, puts
Enter in ice-water bath, controlled at 5~10 DEG C, and sodium ethoxide is added, be stirred to react 6~8h, adds into three-necked flask after reaction
Enter distilled water, stand overnight, collects oil phase；
(2) in mass ratio 1:8, oil phase and ethyl alcohol mixing are weighed, potassium carbonate is added after mixing, is heated to flowing back, back flow reaction 30
~40min, it is 4.5~5.0 that vinegar acid for adjusting pH value is used after reaction, and rotary evaporated to dryness after adjusting collects solid, after being washed with water
It is dry, you can to obtain imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester.
2. a kind of synthesis work of medicine intermediate imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester according to claim 1
Skill, it is characterised in that：The molar ratio of the sodium ethoxide and (2- oxos -1 (2H)-pyridyl group) acetonitrile is 5~7:1.
3. a kind of synthesis work of medicine intermediate imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester according to claim 1
Skill, it is characterised in that：The potassium carbonate addition is the 10~20% of oil phase quality.
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| CN201810201551.2A CN108276405A (en) | 2018-03-12 | 2018-03-12 | A kind of synthesis technology of medicine intermediate imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester |
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| CN201810201551.2A CN108276405A (en) | 2018-03-12 | 2018-03-12 | A kind of synthesis technology of medicine intermediate imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1045782A (en) * | 1989-02-17 | 1990-10-03 | 武田药品工业株式会社 | The preparation of imidazopyridine and application thereof |
| WO1998058905A1 (en) * | 1997-06-25 | 1998-12-30 | Yamanouchi Pharmaceutical Co., Ltd. | Novel amidrazone derivatives having antifungal activity |
| CN102101860A (en) * | 2010-12-23 | 2011-06-22 | 北京满格医药科技有限公司 | Novel method for synthesizing key intermediate of minodronate |
| CN104135859A (en) * | 2011-12-28 | 2014-11-05 | 全球血液疗法公司 | Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation |
| CN104271561A (en) * | 2012-03-06 | 2015-01-07 | 佐蒂斯有限责任公司 | Phenicol antibacterials |
| CN107778313A (en) * | 2016-08-29 | 2018-03-09 | 鲁南制药集团股份有限公司 | A kind of process for purification of the acetic acid of Minodronate intermediate imidazo [1,2 a] pyridine 3 |
-
2018
- 2018-03-12 CN CN201810201551.2A patent/CN108276405A/en not_active Withdrawn
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1045782A (en) * | 1989-02-17 | 1990-10-03 | 武田药品工业株式会社 | The preparation of imidazopyridine and application thereof |
| WO1998058905A1 (en) * | 1997-06-25 | 1998-12-30 | Yamanouchi Pharmaceutical Co., Ltd. | Novel amidrazone derivatives having antifungal activity |
| CN102101860A (en) * | 2010-12-23 | 2011-06-22 | 北京满格医药科技有限公司 | Novel method for synthesizing key intermediate of minodronate |
| CN104135859A (en) * | 2011-12-28 | 2014-11-05 | 全球血液疗法公司 | Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation |
| CN104271561A (en) * | 2012-03-06 | 2015-01-07 | 佐蒂斯有限责任公司 | Phenicol antibacterials |
| CN107778313A (en) * | 2016-08-29 | 2018-03-09 | 鲁南制药集团股份有限公司 | A kind of process for purification of the acetic acid of Minodronate intermediate imidazo [1,2 a] pyridine 3 |
Non-Patent Citations (4)
| Title |
|---|
| CRISTINA M. AL MATARNEH等: "Reactions of ethyl cyanoformate with cycloimmonium salts: a direct pathway to fused or substituted azaheterocycles", 《TETRAHEDRON》 * |
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| JOSEPH G. LOMBARDINO等: "Preparation and New Reactions of Imidazo[l,2-o]pyridines", 《J.AM.CHEM.SOC.》 * |
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